Patients with End Stage Renal Disease (ESRD) managed with chronic hemodialysis often have severe aluminum toxicity. This may be caused by the aluminum-containing medication given to these patients to keep blood phosphate levels in balance, by aluminum in the dialysate fluid, by diet, or by increased aluminum absorption from the intestines.
Depending of the level of aluminum in the blood, its toxicity may have different manifestations. Aluminum levels above 60 .mu.g/L may cause anemia unresponsive to treatment with erythropoietin, and osteodystrophy with severe enough bone pain to keep patients wheelchair bound. A level of 100 .mu.g/L or more will result in progressive brain damage leading to death in 12 months or less. In the U.S. alone, hundreds of thousands of patients with ESRD are treated with chronic hemodialysis.
A second population at potential risk for aluminum toxicity includes individuals with dental and heart valve implants, and orthopedic replacement joints. These prostheses often have parts containing aluminum alloys to increase weight bearing or to decrease calcification. Aluminum leaching from such implants may cause toxicity over time, particularly in diabetic or elderly individuals with compromised kidney function.
Patients with aluminum intoxication are currently treated with intravenous infusions of desferrioxamine (DFO) given 1-3 times weekly. The complex formed between the DFO and the aluminum circulating in the blood is expected to be removed by dialysis. Reduction of aluminum to "sub-toxic levels" (under 30 .mu.g/L) may take 8 to 12 months, during which time the patient is exposed to the toxicity of aluminum as well as the toxicity of DFO. For that reason, today this treatment is restricted to patients with high aluminum levels (100 .mu.g/L or more) . Acute side-effects of DFO infusion include hypotension and acute loss of visual acuity which is, however, reversible. Increased incidence of systemic bacterial infections as well as lethal fungal infections may also accompany treatment of patients with DFO.
Medical devices comprising cartridges containing inactivated charcoal have been introduced for the removal of aluminum from a patient's blood. However the devices cause damage to the blood cells as they flow through the charcoal in the cartridges.
In addition to aluminum, other metals present in contaminated environments can accumulate in a person's body and cause substantial health problems. Such metals include, for example, iron, lead, copper, cadmium, mercury, nickel, zinc, and plutonium. The cations of all of these metals undergo reaction with typical multivalent chelating agents to form metal chelate complexes that can be separated and removed from the reaction site.
U.S. Pat. No. 4,612,122 to Ambrus and Horvath, the disclosure of which is incorporated herein by reference, describes an extracorporeal device for removing metal cations from blood using an immobilized chelating agent. As blood flows through the device, the cations react with the chelating agent to form a complex that is retained in the device, resulting in detoxification of the blood.
A device similar to that described in U.S. Pat. No. 4,612,122 and containing the chelating agent desferrioxamine (DFS) has been employed to remove aluminum and iron from blood, as described in Anthone et al., "Immobilized Desferrioxamine (DFO) for the Extracorporeal Removal of Aluminum" in ASAIO, 1987, Vol. 10, No. 3, pages 744-748; Anthone et al., "Treatment of Aluminum Overload Using a Cartridge With Immobilized Desferrioxamine" in J. Am. Soc. Nephrol., 1995, Vol. 5, pages 1271-1277; and Ambrus et al., "Extracorporeal Removal of Iron with Immobilized Desferrioxamine" in ASATO, 1987, Vol. 10, No. 3, pages 749-752, the disclosures of which are incorporated herein by reference.
Immobilized chelating agents are useful for removing metal cations from substances other than blood. For example, Glennon et al., "Biochelator Cartridge for the Solid-Phase Extraction of Trace Metals" in Analyst, 1990, Vol. 115, pages 627-630, the disclosure of which is incorporated herein by reference, describes hydroxamic acid chelating agents, including desferrioxamine (DFO), immobilized in silica and used for separation of various metal cations from sea water. Also, Fadeeva et. al., "Preparation, Properties and Analytical Application of Silica with Chemically Grafted Hydroxamic Acid Groups" in Analytica Chimica Acta, 1989, Vol. 219, pages 201-212, the disclosure of which is incorporated herein by reference, describes the attachment of propanohydroxamic acid groups to silica having a surface area of 80 m.sup.2 /g. The resulting sorbents are used to remove trace amounts of metals such as molybdenum (VI), zirconium (IV), and vanadium (V).
The efficiency of metal cation removal using the device described in U.S. Pat. No. 4,612,122 and the above-cited references depends considerably on the amount of a chelating agent such as DFO that is immobilized within the device. Accordingly, a process that can provide for the immobilization of larger amounts of DFO per amount of silica substrate, while allowing the device to function effectively to remove aluminum and other cations, would be highly desirable. This result is achieved by the present invention.